NK cell activation by RSV-specific antibodies is decreased in infants with severe respiratory infections and correlates with Fc-glycosylation

Background: Respiratory syncytial virus (RSV) is a major cause of severe acute lower respiratory tract infections in infants and there is no vaccine available. In early life, the most important contributors to protection against infectious diseases are the innate immune system and maternal antibodies. However, the mechanisms by which antibodies can protect against severe RSV disease are incompletely understood, as both antibody levels and neutralization capacity correlate poorly with protection. Methods: We performed an observational case-control study including infants hospitalized for RSV infection (n=43), hernia surgery (n=16), or RSV-negative viral respiratory tract infections (n=18). First, we determined RSV antigen-specific antibody levels in infant plasma using a multiplex immunoassay. Subsequently, we measured the capacity of these antibodies to activate natural killer (NK) cells. Finally, we assessed Fc-glycosylation of the RSV-specific antibodies by mass spectrometry. Results: We found that the concentrations of RSV antigen-specific antibodies did not differ between cases and controls. Importantly, RSV-specific maternal antibodies potently activated NK cells in vitro. Furthermore, antibodies from infants hospitalized for severe lower respiratory tract infections (RSV and/or other) induced significantly less NK cell interferon gamma production than those from uninfected controls. Finally, NK cell activation correlated with Fc-fucosylation of RSV-specific antibodies, but their glycosylation status did not significantly differ between cases and controls. Conclusions: Our results suggest that Fc-dependent antibody function and quality, exemplified by NK cell activation and glycosylation, contribute to protection against severe RSV disease and warrant further studies to evaluate the potential of harnessing these activities to develop an effective vaccine.